Estrogens modulate a range of metabolic processes in humans, notably, reproduction, cardiovascular health, bone integrity, cognition and behavior. Estrogen also plays a central role in a wide range of human diseases, including various types of cancer (for example, breast, ovarian, colorectal, prostate, kidney and endometrial), osteoporosis, neurodegenerative diseases, cardiovascular disease, insulin resistance, lupus erythematosus, endometriosis, and obesity. In many of these disorders, estrogen mediates the disease through the estrogen receptor. Deroo, et al., Estrogen Receptors and Human Disease, J. Clin. Invest. 2006 Mar. 1, 116(3):561-570.
Estrogen receptors orchestrate both transcriptional and non-genomic functions in response to estrogens. These pleotropic and tissue-specific effects are thought to occur because of the differential expression of different subtypes of the estrogen receptor (ERα and ERβ) and their co-regulators. Moggs, et al., Estrogen receptors: Orchestrators of pleiotropic cellular responses, EMBO Report, 2001 Sep. 15; 2(9): 775-781. There is intricate complexity to the dynamics of ER-mediated transcription. Id. In addition, estrogen receptors also appear to have a direct effect on cytosolic signaling under some circumstances. Id.
An extensive amount of pharmaceutical research has been directed to identifying compounds that block the estrogen receptor and shut down undesired actions of the receptor while sometimes trying to maintain the beneficial effects of the receptor. Other efforts have been directed to trying to completely shut down all estrogen receptor activity, to treat potentially life-threatening diseases where it is more important to block all activity than preserve certain beneficial effects.
In June 2011, Aragon Pharmaceuticals disclosed benzopyran derivatives and acolbifene analogs for treatment of tamoxifen-resistant breast cancer (see WO2011/156518, U.S. Pat. Nos. 8,455,534 and 8,299,112). Aragon became Seragon in 2013, and was purchased by Genentech in 2014. See also U.S. Pat. Nos. 9,078,871; 8,853,423; 8,703,810 and US 2015/0005286.
Genentech disclosed a series of tetrahydro-pyrido[3,4-b]indol-1-yl compounds with estrogen receptor modulation activity in US2016/0175289 and US2015/0258080. Genentech is now developing Brilanstrant (GDC-0810) for the treatment of locally advanced or metastatic estrogenic receptor positive breast cancer.
Genentech, Inc. also disclosed a series of compounds with a moiety described as a SERMF (selective estrogen receptor modulator fragment) in US 2016/0304450 for the treatment of ER-related diseases.
In US 2016/0347742, Genentech disclosed chromene-, thiochromene-, dihydroquinoline-, and naphthalene-based compounds and their pharmaceutical compositions for the treatment of estrogen-mediated diseases, including but not limited to breast cancer, uterine cancer, and endometrial cancer. Genentech described chromene-based compounds with azetidine functionality in US 2016/0090377 and US 2016/0367526, claiming priority from WO2014/205136. These compounds, with a fluorine substituent on the azetidine ring, were active in breast cancer, ovarian cancer, and uterine cancer cell lines. Genentech disclosed additional compounds with fluorine-substituted azetidine moieties on chromene rings in US 2016/0090378 and US 2016/0175284.
GlaxoSmithKline PLC disclosed a series of benzothiophene analogs, some of which are substituted with short polyethylene glycol basic chains, for the treatment of estrogen receptor-mediated conditions in US 2016/0368911.
Eli Lilly and Company disclosed benzothiophene compounds and their pharmaceutical compositions in U.S. Pat. No. 6,403,614 for the treatment of postmenopausal syndrome and related estrogen-mediated diseases including cancer. Novartis International AG also disclosed benzothiphene derivatives as SERDs (selective estrogen receptor degraders) for the treatment of diseases indicated by estrogen dysfunction in WO 2014/130310.
Fulvestrant, a complete estrogen receptor antagonist with no agonist activity, was disclosed by Imperial Chemical Industries (ICI) in U.S. Pat. No. 4,659,516 and is sold by Astra Zeneca under the name Faslodex. It is indicated for the treatment of hormone receptor positive metastatic breast cancer in post-menopausal women with disease progression following anti-estrogen therapy. Fulvestrant has limited water solubility and requires monthly intramuscular (IM) injections. Fulvestrant's aqueous insolubility creates a challenge to achieve and maintain efficacious serum concentrations.
An example of a selective estrogen receptor modulator (SERMs) which act as antagonists or agonists in a gene-specific and tissue-specific fashion is tamoxifen, initially sold by AstraZeneca under the name Nolvadex. Tamoxifen was also disclosed by ICI in U.S. Pat. No. 4,659,516, (see also U.S. Pat. Nos. 6,774,122 and 7,456,160). AstraZeneca is currently developing AZD9496, a novel, oral selective estrogen receptor downregulator in patients with estrogen receptor positive breast cancer (WO 2014/191726).
Aromatase inhibitors which block the production of estrogen and therefore block ER-dependent growth include letrozole, anastrozole, and exemestane.
A number of SERDs, SERMs, and aromatase inhibitors have been disclosed. The SERM raloxifene was disclosed by Eli Lilly in 1981 (U.S. Pat. Nos. 4,418,068; 5,478,847; 5,393,763; and 5,457,117) for prevention of breast cancer and treatment of osteoporosis.
Additional anti-estrogenic compounds are disclosed in WO 2012/084711; WO 2002/013802; WO 2002/004418; WO 2002/003992; WO 2002/003991; WO 2002/003990; WO 2002/003989; WO 2002/003988; WO 2002/003986; WO 2002/003977; WO 2002/003976; WO 2002/003975; WO 2006/078834; U.S. Pat. No. 6,821,989; US 2002/0128276; U.S. Pat. No. 6,777,424; US 2002/0016340; U.S. Pat. Nos. 6,326,392; 6,756,401; US 2002/0013327; U.S. Pat. Nos. 6,512,002; 6,632,834; US 2001/0056099; U.S. Pat. Nos. 6,583,170; 6,479,535; WO 1999/024027; U.S. Pat. No. 6,005,102; EP 0802184; U.S. Pat. Nos. 5,998,402; 5,780,497 and 5,880,137.
Additional estrogen receptor inhibitors were published by Xiong, et. al., “Novel Selective Estrogen Receptor Downregulators (SERDs) Developed Against Treatment-Resistant Breast Cancer (J. Med. Chem, Jan. 24, 2017 web release). Examples of such selective estrogen receptor downregulators and their biological activities were provided at the Apr. 16, 2016 American Associate for Cancer Research (AARC) Conference in a poster presentation by Lauren M. Gutgesell et. al. titled “Estrogen receptor ligands and their responses in de novo and tamoxifen resistant cell models.” Additional examples in the series of SERDs were described in the oral presentation and power-point presented by Dr. Thatcher at the 252nd ACS National Meeting in Philadelphia, Pa. on Aug. 21, 2016.
In light of the role estrogen receptors play in a range of human disease, including breast tumors and breast cancer, it would be useful to have additional compounds that are useful to treat these disorders.